This invention relates to aminobutyric acid derivatives, processes for the preparation thereof and pharmaceutical agents comprising aminobutyric acid derivatives as active ingredient.
More particularly, this invention relates to:
[1] aminobutyric acid derivatives of the formula (I): 
wherein all the symbols are as hereinafter defined, and non-toxic salts thereof, processes for the preparation thereof and pharmaceutical agents comprising aminobutyric acid derivatives as active ingredient, and
[2] a compound which is selected from
(1)5-ethoxymethoxy-4(S)-[N-(4-iodophenylcarbonyl)amino]pentanoic acid,
(2)5-ethoxymethoxy-4(S)-[N-(4-cyanophenylcarbonyl)amino]-2(R)-methoxymethylpentanoic acid,
(3)2(R)-ethoxymethyl-5-ethoxymethoxy-4 (S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(4) 5-ethoxymethoxy-2 (S)-(3-thienylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(5)5-ethoxymethoxy-2(S)-(3-furylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(6)2(S)-benzyl-5-pivaroyloxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(7)5-acetyloxy-2(S)-benzyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(8)5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-phenoxyhenylcarbonyl)amino]pentanoic acid,
(9)5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-(2-furyl)phenylcarbonyl)amino]pentanoic acid,
(10)5-ethoxymethoxy-4(S)-[N-(4-cyanophenylcarbonyl)amino]-2(R)-ethoxymethylpentanoic acid,
(11)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(12)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-chlorophenylcarbonyl)amino]pentanoic acid,
(13)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-bromophenylcarbonyl)amino]pentanoic acid,
(14)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-cyanophenylcarbonyl)amino]pentanoic acid,
(15)5-ethoxymethoxy-2(S)-benzyl-4(S)-[N-(4-chlorocyclohexylcarbonyl)amino]pentanoic acid,
(16)5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(17)5-methoxyethoxymethoxy-2(S)-methyl-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(18)trans-2-[(4-nitrophenylcarbonyl)aminomethyl]cyclohexanoic acid,
(19)trans-2-[(4-(3-methoxy-1-propynyl)phenylcarbonyl)aminomethyl]cyclohexanoic acid,
(20)trans-2-[(4-nitrophenylcarbonyl)amino]cyclohexylacetic acid,
(21)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,
(22)N-hydroxy-2(R)-ethoxymethyl-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(23)N-hydroxy-5-ethoxymethoxy-2(S)-(3-thienylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(24)N-hydroxy-5-ethoxymethoxy-2(S)-(3-furylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(25)N-hydroxy-2(S)-benzyl-5-pivaroyloxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(26)N-hydroxy-5-acetyloxy-2(S)-benzyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(27)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-phenoxyphenylcarbonyl)amino]pentanamide,
(28)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-(2-furyl)phenylcarbonyl)amino]pentanamide,
(29)N-hydroxy-5-ethoxymethoxy-2(R)-ethoxymethyl-4(S)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,
(30)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(31)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-chlorophenylcarbonyl)amino]pentanamide,
(32)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-bromophenylcarbonyl)amino]pentanamide,
(33)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,
(34)N-hydroxy-5-ethoxymethoxy-2(S)-benzyl-4(S)-[N-(4-chlorocyclohexylcarbonyl)amino]pentanamide,
(35)N-hydroxy-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(36)N-hydroxy-2(S)-methyl-5-methoxyethoxymethoxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,
(37)N-hydroxy-5-hydroxy-2(R)-methoxymethyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(38)N-hydroxy-5-hydroxy-2(R)-methoxymethyl-4(S)-[N-(4-chlorophenylcarbonyl)amino]pentanamide,
(39)N-hydroxy-2(S)-(2-benzothiophen-3-yl)methyl)-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,
(40)N-hydroxy-2(S)-allyl-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,
(41)N-hydroxy-2(S)-(3-phenylpropyl)-5-hydroxy-4(S)-[N-methyl-N-(4-bromophenylcarbonyl)amino]pentanamide,
(42)N-hydroxy-2(S)-(3-phenylpropyl)-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,
(43)N-hydroxy-2(S)-methyl-5-hydroxy-4(S)-[N-methyl-N-[(5-nitro-2-thienyl)carbonyl]amino]pentanamide,
(44)N-hydroxy-2(S)-benzyl-5-hydroxy-4(S)-[N-methyl-N-[(5-bromo-2-thienyl)carbonyl]amino]pentanamide,
(45)trans-1-(N-hydroxyaminocarbonyl)-2-[(4-nitrophenylcarbonyl)aminomethyl]cyclohexane,
(46)trans-1-(N-hydroxyaminocarbonyl)-2-[(4-(3-methoxy-1-propynyl)phenylcarbonyl)aminomethyl]cyclohexane,
(47)trans-1-(N-hydroxyaminocarbonylmethyl)-2-[(4-nitrophenylcarbonyl)amino]cyclohexane,
and methyl ester, t-butyl ester, benzyl ester, allyl ester, and non-toxic salts thereof, and pharmaceutical agents comprising the compound and non-toxic salts thereof as active ingredient.
The matrix metalloproteinases (MMPs) are neutral metalloproteinases and zinc (Zn2+) is essential in the active site for their activation. They degrade collagen, laminin, proteoglycans, fibronectin, elastin, gelatin etc. under physiological conditions and therefore, are effective on growth and tissue remodeling of articulation tissue, bone tissue and connective tissue. At least 10 classes of MMPs, which differ in primary structure, are identified. Concretely, there are Interstitial Collagenase (MMP-1), Neutrophil Collagenase (MMP-8), Gelatinase A (MMP-2), Gelatinase B (MMP-9), Stromelysin-1 (MMP-3), Stromelysin-2 (MMP-10), Matrilysin (MMP-7), metalloelastase (MMP-12) etc.
As common characteristics of these enzymes, MMPs
(1) have Zn2+ in the active site and the activity depends on calcium ion (Ca2+)
(2) are secreted as an inactive proenzyme and activated outside of cells,
(3) have high homology on amino acid sequence,
(4) have an ability to degrade on various extracellular matrix components in vivo,
(5) are regulated by tissue inhibitors of metalloproteinases (TIMP) which are specific to MMPs.
MMP inhibitors are useful for prevention and/or treatment of various diseases induced by overexpression and excess activation of MMP. Such diseases are, for example, rheumatoid diseases, arthrosteitis, osteoarthritis, unusual bone resorption, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, cornea ulcer, metastasis, invasion or growth of tumor cells, autoimmune disease (Crohn""s disease, Sjogren""s syndrome), disease caused by vascular emigration or infiltration of leukocytes, arterialization, multiple sclerosis, aorta aneurysm, endometriosis, restenosis after PTCA, unstable angina, acute myocardial infarction, transient ischemic attack.
Some compounds possessing inhibitory activity against MMP are known. A sequence in the vicinity of cleavage site of collagen (Gly-Ile-Ala-Gly or Gly-Leu-Ala-Gly) has high affinity for collagenase. Much research and development on substrate analogous MMP inhibitors, which are chemically modified so as to have zinc affinity groups on a cleaving site of the substrate, has energetically been carried out [Inhibitors of matrix metalloproteinases (MMP""s), Nigel R A Beeley, Phillip R J Ansell, Andrew J P Docherty et. al., Curr. Opin. Ther. Patents., A, 7-16 (1994), Current Drugs Ltd ISSN 0962-2594]. However, these substrate-analogues inhibitors might have various problems. Therefor, it is desired to obtain a non-peptide inhibitor and some compounds are reported.
For example, in the specification of EP 757037 as the Example, sulfonylamino acid derivatives of the formula (W): 
are disclosed to have an activity of inhibiting matrix metalloproteinase.
In the specification of EP 757984 as the Example, hydroxamic acid derivatives of the formula (X): 
are disclosed to have an activity of inhibiting matrix metalloproteinase.
Energetic investigations have been carried out in order to make an inhibitor for matrix metalloproteinase, e.g. gelatinase, stromelysin or collagenase. The present inventors have found that aminobutyric acid derivatives of the formula (I), which are carboxylic amino derivatives of xcex3-amino acid accomplished the present purpose.
The present invention relates to:
[1] aminobutyric acid derivatives of the formula (I): 
xe2x80x83wherein
R1 is xe2x80x94COOR10, xe2x80x94CONHOR10, xe2x80x94CONHNHR10, xe2x80x94(CH2)nSR50 or xe2x80x94Yxe2x80x94PO(OR51)2;
R10 is (i) hydrogen, (ii) C1-8 alkyl, (iii) C2-8 alkenyl, (iv) phenyl, (v) C1-8 alkyl substituted by phenyl or C1-8 alkoxy, or (vi) oxycarbonyl substituted by phenyl, benzyl or C1-8 alkyl;
n is 0-3;
R50 is (i) hydrogen, (ii) C1-8 alkyl, (iii) xe2x80x94COR52, in which R52 is C1-8 alkyl or phenyl, (iv) xe2x80x94SR53, in which R53 is hydrogen, C1-8 alkyl or phenyl;
R51 is hydrogen, C1-8 alkyl or phenyl;
Y is a single bond, xe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94;
R2, R3, R4, R5, R6 and R7 each, independently, is
(1) hydrogen,
(2) C1-8 alkyl,
(3) C2-8 alkenyl,
(4) xe2x80x94OR11,
(5) xe2x80x94SR11,
(6) xe2x80x94NR12R13,
(7) Cyc1,
(8) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1,
(9) C2-8 alkenyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1,
(10) C2-8 alkynyl,
(11) C1-8 alkyl substituted by one or more groups selected from C3-8 alkenyloxy, with the proviso that a group having a double bond at 1-position is excluded; and C3-8 alkynyloxy, with the proviso that a group having a triple bond at 1-position is excluded; or
R3 and R4, taken together is C1-8 alkylene, R5and R6, taken together is C1-8 alkylene, R3 and R6, taken together is C1-8 alkylene, R2 and R3, taken together is C2-8 alkylene, R4 and R5, taken together is C2-8 alkylene, or R6 and R7, taken together is C2-8 alkylene;
in which Cyc1 is carbocyclic ring or heterocyclic ring and these carbocyclic ring and heterocyclic ring may be substituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v) amidino, (vi) halogen atoms, (vii) cyano (viii) hydroxy, (ix) benzyloxy, (x) xe2x80x94NR101R102, in which R101 and R102 each, independently, is hydrogen or C1-8 alkyl, (xi) xe2x80x94COOR103, in which R103 is hydrogen or C1-8 alkyl, (xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv) phenyl, (xv) phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi) phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8 alkyl substituted by phenyl or cyano, (xix) heterocyclic ring, (xx) keto, (xxi) C1-8 alkoxy substituted by xe2x80x94CONR104R105, in which R104 and R105 each, independently, is hydrogen, C1-8 alkyl or phenyl;
R11 is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) Cyc1,
(iv) xe2x80x94COR18,
(v) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR15, xe2x80x94SR15, xe2x80x94NR16R17, xe2x80x94COR18, guanidino and Cyc1;
R15 is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1 or C1-8 alkoxy;
R16 is hydrogen or C1-8 alkyl;
R17 is hydrogen, C1-8 alkyl or xe2x80x94COR19, in which R19 is C1-8 alkyl, Cyc1, C1-8 alkyl substituted by Cyc1;
R18 is hydroxy, C1-8 alkyl, C1-8  alkoxy or xe2x80x94N20R21, in which R20 and R21, each independently, is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1;
R12 is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1;
R13 is hydrogen, C1-8 alkyl, Cyc1, C1-8 alkyl substitutedby Cyc1, or xe2x80x94COR22, in which R22 is C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1;
R14 is hydroxy, C1-8 alkyl, C1-8 alkoxy, Cyc1, C1-8 alkyl substituted by Cyc1, or xe2x80x94NR23R24, in which R23 and R24, each ndependently, is (i) hydrogen, (ii) C1-8 alkyl, (iii) Cyc1 or (iv) C1-8 alkyl substituted by Cyc1 or hydroxy;
(1) when R8 is
1) hydrogen,
2) C1-8 alkyl,
3) C1-8 alkoxycarbonyl,
4) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR26, xe2x80x94SR26, xe2x80x94NR27R28 and xe2x80x94COR29, or
5) C1-8 alkoxycarbonyl substituted by Cyc2,
R9 is 
(2) when R8 is 
R9 is
1) C1-8 alkyl,
2) C1-8 alkoxy,
3) C1-8 alkoxy substituted by Cyc2,
4) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR26, xe2x80x94SR26, xe2x80x94NR27R28, xe2x80x94COR29 and Cyc2, or
5) 
xe2x80x83in which Cyc2 is carbocyclic ring or heterocyclic ring and these carbocyclic ring and heterocyclic ring may be substituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v) amidino, (vi) halogen atoms, (vii) cyano, (viii) hydroxy, (ix) benzyloxy, (x) xe2x80x94NR201R202, in which R201 and R202 each, independently, is hydrogen or C1-8 alkyl, (xi) xe2x80x94COOR203, in which R203 is hydrogen or C1-8 alkyl, (xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv) phenyl, (xv) phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi) phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8 alkyl substituted by phenyl or cyano, (xix) heterocyclic ring, (xx) keto, (xxi) C1-8 alkoxy substituted by xe2x80x94CONR204R205 in which R204 and R205 each, independently, is hydrogen, C1-8 alkyl or phenyl;
R26 is hydrogen, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2;
R27 is hydrogen, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2;
R28 is hydrogen, C1-8 alkyl, Cyc2, C1-8 alkyl substituted by Cyc2, or xe2x80x94COR30, in which R30 is C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2;
R29 is hydroxy, C1-8 alkyl, Cyc2, C1-8 alkyl substituted by Cyc2, or xe2x80x94NR31R32, in which R31 and R32, each independently, is hydrogen, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2; 
xe2x80x83is carbocyclic ring or heterocyclic ring;
R25 is xe2x80x94Exe2x80x94G;
E is
1) a single bond,
2) xe2x80x94CONR33xe2x80x94,
3) xe2x80x94NR33COxe2x80x94,
4) xe2x80x94COxe2x80x94Oxe2x80x94,
5) xe2x80x94Oxe2x80x94COxe2x80x94,
6) xe2x80x94NR33xe2x80x94COxe2x80x94NR34xe2x80x94,
7) xe2x80x94COxe2x80x94CH2xe2x80x94,
8) xe2x80x94COxe2x80x94,
9) xe2x80x94Oxe2x80x94COxe2x80x94NR33xe2x80x94,
10) xe2x80x94NR33xe2x80x94COxe2x80x94Oxe2x80x94,
11) xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94,
12) xe2x80x94CSxe2x80x94NR33xe2x80x94,
13) xe2x80x94NR33xe2x80x94CSxe2x80x94,
14) xe2x80x94CSxe2x80x94Oxe2x80x94,
15) xe2x80x94Oxe2x80x94CSxe2x80x94,
16) xe2x80x94NR33xe2x80x94CSxe2x80x94NR34xe2x80x94,
17) xe2x80x94CSxe2x80x94CH2xe2x80x94,
18) xe2x80x94CSxe2x80x94,
19) xe2x80x94Oxe2x80x94CSxe2x80x94NR33xe2x80x94,
20) xe2x80x94NR33xe2x80x94CSxe2x80x94Oxe2x80x94,
21) xe2x80x94Oxe2x80x94CSxe2x80x94Oxe2x80x94,
22) xe2x80x94CH2xe2x80x94CH2xe2x80x94,
23) xe2x80x94HCxe2x95x90CHxe2x80x94,
24) xe2x80x94Cxe2x89xa1Cxe2x80x94,
25) xe2x80x94SO2xe2x80x94NR33xe2x80x94,
26) xe2x80x94NR33xe2x80x94SO2xe2x80x94,
27) xe2x80x94SO2xe2x80x94CH2xe2x80x94 or
28) xe2x80x94CH2xe2x80x94SO2xe2x80x94;
R33 and R34, each independently, is hydrogen, C1-8 alkyl, Cyc3 or C1-8 alkyl substituted by Cyc3;
Cyc3 is carbocyclic ring or heterocyclic ring and these carbocyclic ring and heterocyclic ring may be substituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v) amidino, (vi) halogen atoms, (vii) cyano, (viii) hydroxy, (ix) benzyloxy, (x) xe2x80x94NR301R302, in which R301 and R302 each, independently, is hydrogen or C1-8 alkyl, (xi) xe2x80x94COOR303, in which R303 is hydrogen or C1-8 alkyl, (xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv) phenyl, (xv) phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi) phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8 alkyl substituted by phenyl or cyano, (xix) heterocyclic ring, (xx) keto, (xxi) C1-8 alkoxy substituted by xe2x80x94CONR304R305, in which R304 and R305 each, independently, is hydrogen, C1-8 alkyl or phenyl;
G is
1) hydrogen,
2) C1-8 alkyl,
3) Cyc4,
4) xe2x80x94OR35,
5) xe2x80x94SR35,
6) halogen atoms,
7) nitro,
8) cyano,
9) xe2x80x94NR36R37,
10) xe2x80x94COR38,
11) C1-8 alkyl substituted by one or more groups selected from Cyc4, xe2x80x94OR35, xe2x80x94SR351 halogen atoms, xe2x80x94NR36R37 and xe2x80x94COR38;
in which Cyc4 is carbocyclic ring or heterocyclic ring and these carbocyclic ring and heterocyclic ring may be substituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v) amidino, (vi) halogen atoms, (vii) cyano, (viii) hydroxy, (ix) benzyloxy, (x) xe2x80x94NR401R402, in which R401 and R402 each, independently, is hydrogen or C1-8 alkyl, (xi) xe2x80x94COOR403, in which R403 is hydrogen or C1-8 alkyl, (xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv) phenyl, (xv) phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi) phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8 alkyl substituted by phenyl or cyano, (xix) heterocyclic ring, (xx) keto, (xxi) C1-8 alkoxy substituted by xe2x80x94CONR404R405 in which R404 and R405 each, independently, is hydrogen, C1-8 alkyl or phenyl;
R35 is hydrogen, C1-8 alkyl, C1-8 alkoxy, Cyc4 or C1-8 alkyl substituted by Cyc4;
R36 is hydrogen, C1-8 alkyl, Cyc4, C1-8 alkyl substituted by Cyc4;
R37 is hydrogen, C1-8 alkyl, Cyc4, C1-8 alkyl substituted by Cyc4, or xe2x80x94COR39, in which R39 is C1-8 alkyl, Cyc4 or C1-8 alkyl substituted by Cyc4;
R38 is hydroxy, C1-8 alkyl, Cyc4, C1-8 alkyl substituted by Cyc4, or xe2x80x94NR40R41, in which R40 and R41, each independently, is hydrogen, C1-8 alkyl, Cyc4 or C1-8 alkyl substituted by Cyc4; or
xe2x80x94Exe2x80x94G taken together, is C1-4 alkylidene;
p is 1-5;
M is C1-8 alkylene;
J is a single bond, an oxygen atom, a sulfur atom or xe2x80x94NR42xe2x80x94, in which R42 is hydrogen or C1-8 alkyl;
 is a single bond, or a double bond which prepared by two hydrogens are released, in the case of two of R2, R3, R4, R5, R6 and R7 which do not bond to a same carbon atom but bond to a neighboring carbon, are hydrogens; with the proviso that
 is not a double bond, when R3 and R4, taken together is C1-8 alkylene, R5 and R6, taken together is C1-8 alkylene, R3 and R6, taken together is C1-8 alkylene;
with the proviso that (1) at least one of R2, R3, R4, R5, R6 and R7is C2-8 alkynyl, or C1-8 alkyl substituted by one or more groups selected from C3-8 alkenyloxy and C3-8 alkynyloxy,
(2) when 
xe2x80x83is benzene, and E is a single bond, then G is not hydrogen;
xe2x80x83non-toxic acid thereof, a process for the preparation thereof, and a pharmaceutical agent comprising the same,
[2] a compound which is selected from
(1)5-ethoxymethoxy-4(S)-[N-(4-iodophenylcarbonyl)amino]pentanoic acid,
(2)5-ethoxymethoxy-4(S)-[N-(4-cyanophenylcarbonyl)amino]-2(R)-methoxymethylpentanoic acid,
(3)2(R)-ethoxymethyl-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(4)5-ethoxymethoxy-2(S)-(3-thienylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(5)5-ethoxymethoxy-2(S)-(3-furylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(6)2(S)-benzyl-5-pivaroyloxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(7)5-acetyloxy-2(S)-benzyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(8)5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-phenoxy-henylcarbonyl)amino]pentanoic acid,
(9)5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-(2-furyl)phenylcarbonyl)amino]pentanoic acid,
(10)5-ethoxymethoxy-4(S)-[N-(4-cyanophenylcarbonyl)amino]-2(R)-ethoxymethylpentanoic acid,
(11)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(12)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-chlorophenylcarbonyl)amino]pentanoic acid,
(13)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-bromophenylcarbonyl)amino]pentanoic acid,
(14)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-cyanophenylcarbonyl)amino]pentanoic acid,
(15)5-ethoxymethoxy-2(S)-benzyl-4(S)-[N-(4-chlorocyclohexylcarbonyl)amino]pentanoic acid,
(16)5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(17)5-methoxyethoxymethoxy-2(S)-methyl-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(18)trans-2-[(4-nitrophenylcarbonyl)aminomethyl]cyclohexanoic acid,
(19)trans-2-[(4-(3-methoxy-1-propynyl)phenylcarbonyl)aminomethyl]cyclohexanoic acid,
(20) trans-2-[((nitrophenylcarbonyl)amino]cyclohexylacetic acid,
(21)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,
(22)N-hydroxy-2(R)-ethoxymethyl-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(23)N-hydroxy-5-ethoxymethoxy-2(S)-(3-thienylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(24)N-hydroxy-5-ethoxymethoxy-2(S)-(3-furylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(25)N-hydroxy-2(S)-benzyl-5-pivaroyloxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(26)N-hydroxy-5-acetyloxy-2(S)-benzyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(27)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-phenoxyphenylcarbonyl)amino]pentanamide,
(28)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-(2-furyl)phenylcarbonyl)amino]pentanamide,
(29)N-hydroxy-5-ethoxymethoxy-2(R)-ethoxymethyl-4(S)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,
(30)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(31)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-chlorophenylcarbonyl)amino]pentanamide,
(32)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-bromophenylcarbonyl)amino]pentanamide,
(33)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,
(34)N-hydroxy-5-ethoxymethoxy-2(S)-benzyl-4(S)-[N-(4-chlorocyclohexylcarbonyl)amino]pentanamide,
(35)N-hydroxy-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(36)N-hydroxy-2(S)-methyl-5-methoxyethoxymethoxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,
(37)N-hydroxy-5-hydroxy-2(R)-methoxymethyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(38)N-hydroxy-5-hydroxy-2(R)-methoxymethyl-4(S)-[N-(4-chlorophenylcarbonyl)amino]pentanamide,
(39)N-hydroxy-2(S)-(2-benzothiophen-3-yl)methyl)-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,
(40)N-hydroxy-2(S)-allyl-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,
(41)N-hydroxy-2(S)-(3-phenylpropyl)-5-hydroxy-4(S)-[N-methyl-N-(4-bromophenylcarbonyl)amino]pentanamide,
(42)N-hydroxy-2(S)-(3-phenylpropyl)-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,
(43)N-hydroxy-2(S)-methyl-5-hydroxy-4(S)-[N-methyl-N-[(5-nitro-2-thienyl)carbonyl]amino]pentanamide,
(44)N-hydroxy-2(S)-benzyl-5-hydroxy-4(S)-[N-methyl-N-[(5-bromo-2-thienyl)carbonyl]amino]pentanamide,
(45)trans-1-(N-hydroxyaminocarbonyl)-2-[(4-nitrophenylcarbonyl)aminomethyl]cyclohexane,
(46)trans-1-(N-hydroxyaminocarbonyl)-2-[(4-(3-methoxy-1-propynyl)phenylcarbonyl)aminomethyl]cyclohexane,
(47)trans-1-(N-hydroxyaminocarbonylmethyl)-2-[(4-nitrophenylcarbonyl)amino]cyclohexane,
xe2x80x83and methyl ester, t-butyl ester, benzyl ester, allyl ester, and non-toxic salts thereof, and pharmaceutical agents comprising the compound and non-toxic salts thereof as active ingredient.
More particularly, this invention relates to:
[1] (A) the compound of the formula (I) wherein at least one of R2, R3, R4, R5, R6 and R7 is C1-8 alkyl substituted by one or more groups selected from C3-8 alkenyloxy and C3-8 alkynyloxy, non-toxic salts thereof, a process for the preparation thereof, and a pharmaceutical agent comprising the same, (B) the compound of the formula (I) wherein R2, R3, R4, R5, R6 and R7each, independently, is (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) xe2x80x94OR11, (5) xe2x80x94SR11, (6) xe2x80x94NR12R13, (7) Cyc1, (8) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, (9) C2-8 alkenyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, (10) C2-8 alkynyl, or R3 and R4, taken together is C1-8 alkylene, R5andR6, taken together is C1-8 alkylene, R3 and R61 taken together is C1-8 alkylene, R2 and R3, taken together is C2-8 alkylene, R4 and R5s taken together is C2-8 alkylene, or R6and R7, taken together is C2-8 alkylene, and at least one of R2, R3, R4, R5, R6 and R7 is C2-8 alkynyl,
xe2x80x83non-toxic salts thereof, a process for the preparation thereof, and a pharmaceutical agent comprising the same,
[2] the above compound (1)-compound (47), non-toxic salts thereof and a pharmaceutical agent comprising the same.
More particularly about (B) in the above [1],
(B-a) the compound of the formula (I) wherein R2 is 2-propynyl, and R3, R4, R5, R6 and R7 each, independently, is (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) xe2x80x94OR11, (5) xe2x80x94SR11, (6) xe2x80x94NR12R13, (7) Cyc1, (8) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, or (9) C2-8 alkenyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, or R3 and R4, takentogether is C1-8 alkylene, R5and R6, taken together is C1-8 alkylene, R3 and R6, taken together is C1-8 alkylene, R4 and R5, taken together is C2-8 alkylene, or R6 and R7, taken together is C2-8 alkylene, non-toxic salts thereof, a process for the preparation thereof, and a pharmaceutical agent comprising the same, and
(B-b) the compound of the formula (I) wherein R2, R3, R4, R5, R6 and R7 each, independently, is (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) xe2x80x94OR11, (5) xe2x80x94SR11, (6) xe2x80x94NR12R13, (7) Cyc1, (8) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, (9) C2-8 alkenyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, or (10) C2-8 alkynyl, or R3 and R4, taken together is C1-8 alkylene, R5and R6, taken together is C1-8 alkylene, R3 and R6, taken together is C1-8 alkylene, R2 and R3, taken together is C2-8 alkylene, R4 and R5, taken together is C2-8 alkylene, or R6 and R7, taken together is C2-8 alkylene, and at least one of R2, R3, R4, R5, R6 and R7 is C2-8 alkynyl, with the exclusion of the following compound:
the compound wherein R2 is 2-propynyl, and R3, R4, R5, R6 and R7 each, independently, is the above groups (1)xcx9c(9), or R3 and R4, taken together is C1-8 alkylene, R5 and R6, taken together is C1-8 alkylene, R3 and R6, taken together is C1-8 alkylene, R4 and R5, taken together is C2-8 alkylene, or R6and R7, taken together is C2-8 alkylene;
xe2x80x83non-toxic salts thereof, a process for the preparation thereof, and a pharmaceutical agent comprising the same.
More particularly about the above (B-b),
(B-b1) the compound of the formula (I) wherein R2 is (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) xe2x80x94OR11, (5) xe2x80x94SR11, (6) xe2x80x94NR12R13, (7) Cyc1, (8) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, or (9) C2-8 alkenyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, and R3, R4, R5, R6and R7each, independently, is (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) xe2x80x94OR11, (5) xe2x80x94SR11, (6) xe2x80x94NR12R13, (7) Cyc1, (8) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, (9) C2-8 alkenyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR141 guanidino and Cyc1, or (10) C2-8 alkynyl, or R3and R4, taken together is C1-8 alkylene, R5 and R6, taken together is C1-8 alkylene, R3 and R6, taken together is C1-8 alkylene, R2 and R3, taken together is C2-8 alkylene, R4and R5, taken together is C2-8 alkylene, or R6 and R7, taken together is C2-8 alkylene, and at least one of R3, R4, R5, R6 and R7 is C2-8 alkynyl,
xe2x80x83non-toxic salts thereof, a process for the preparation thereof, and a pharmaceutical agent comprising the same,
(B-b2) the compound of the formula (I) wherein R2 is C2-8 alkynyl, and R3, R4, R5, R6 and R7 each, independently, is (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) xe2x80x94OR11, (5) xe2x80x94SR11, (6) xe2x80x94NR12R13, (7) Cyc1, (8) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, (9) C2-8 alkenyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, or (10) C2-8 alkynyl, or R3 and R4, taken together is C1-8 alkylene, R5and R61, taken together is C1-8 alkylene, R3 and R6, taken together is C1-8 alkylene, R4 and R5, taken together is C2-8 alkylene, or R6 and R7, taken together is C2-8 alkylene, and at least one of R3, R4, R5, R6 and R7 is C2-8 alkynyl, non-toxic salts thereof, a process for the preparation thereof, and a pharmaceutical agent comprising the same, and
(B-b3) the compound of the formula (I) wherein R2 is C2 alkynyl, 1-propynyl, C4-8 alkynyl, and R3, R4, R5, R6 and R7 each, independently, is (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) xe2x80x94OR11, (5) xe2x80x94SR11, (6) xe2x80x94NR12R13, (7) Cyc1, (8) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R131, xe2x80x94COR14, guanidino and Cyc1, or (9) C2-8 alkenyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, or R3 and R4, taken together is C1-8 alkylene, R5and R6, taken together is C1-8 alkylene, R3 and R6, taken together is C1-8 alkylene, R4 and R5, taken together is C2-8 alkylene, or R6 and R7, taken together is C2-8 alkylene,
xe2x80x83non-toxic salts thereof, a process for the preparation thereof, and a pharmaceutical agent comprising the same.
In the present invention, C1-8 alkyl is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomeric groups thereof.
C1-8 alkoxy is methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and isomeric groups thereof.
C1-8 alkyl substituted byphenyl is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomeric groups thereof substituted by one of phenyl.
C1-8 alkyl substituted by C1-8 alkoxy is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomeric groups thereof substituted by one of methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and isomeric groups thereof.
C1-8 alkyl substituted by cyano is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomeric groups thereof substituted by one of cyano.
C1-8 alkyl substituted by C3-8 alkenyloxy is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomeric groups thereof substituted by 2-propenyloxy, 2-butenyloxy, 3-butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, pentadienyloxy, hexadienyloxy, heptadienyloxy, octadienyloxy, hexatrienyloxy, heptatrienyloxy, octatrienyloxy and isomeric groups thereof.
C1-8 alkyl substituted by C3-8 alkynyloxy is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomeric groups thereof substituted by 2-propynyloxy, 2-butynyloxy, 3-butynyloxy, pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy and isomeric groups thereof.
C1-8 alkyl substituted by hydroxy is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomeric groups thereof substituted by one of hydroxy.
Oxycarbonyl substituted by phenyl is phenyloxycarbonyl.
Oxycarbonyl substituted by benzyl is benzyloxycarbonyl.
Oxycarbonyl substituted by C1-8 alkyl is methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl and isomeric groups thereof.
C2-8 alkenyl is vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, hexatrienyl, heptatrienyl, octatrienyl and isomeric groups thereof.
C2-8 alkynyl is ethynyl, 1-propynyl, 2-propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and isomeric groups thereof.
C1-8 alkylene is methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, and isomeric groups thereof.
C2-8 alkylene is ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, and isomeric groups thereof.
Halogen atom is chlorine, bromine, fluorine, or iodine.
C1-8 alkoxycarbonyl is methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl and isomeric groups thereof.
C1-4 alkylidene is methylidene, ethylidene, propylidene, butylidene and isomeric groups thereof.
Carbocyclic ring is C3-15 mono-, bi- or tri-carbocyclic ring, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene, pentalene, indene, naphthalene, azulene, fluorene, phenanthrene, anthracene, acenaphthylene, biphenylene, perhydropentalene, perhydroindene, perhydronaphthalene, perhydroazulene, perhydrofluorene, perhydrophenanthrene, perhydroanthracene, perhydroacenaphthylene, perhydrobiphenylene, adamantane, norcarane.
Heterocyclic ring is 5-18 membered mono-, bi- or tri-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s). 5-18 membered mono-, bi- or tri-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) includes 5-18 membered mono-, bi- or tri-heterocyclic aryl containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s), partially or fully saturated thereof.
5-18 membered mono-, bi- or tri-heterocyclic aryl containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s), is, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, oxazepine, thiophene, thiain (thiopyran), thiepin, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzoimidazole, carbazole or acridine.
Partially or fully saturated 5-18 membered mono-, bi- or tri-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) is, for example, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiain (dihydrothiopyran), tetrahydrothiain (tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, benzoxazepine, benzoxadiazepine, benzothiazepine, benzothiadiazepine, benzoazepine, benzodiazepine, indolooxazepine, indolotetrahydrooxazepine, indolooxadiazepine, indolotetrahydrooxadiazepine, indolothiazepine, indolotetrahydrothiazepine, indolothiadiazepine, indolotetrahydrothiadiazepine, indoloazepine, indolotetrahydroazepine, indolodiazepine, indolotetrahydrodiazepine, benzofurazan, benzothiadiazole, benzotriazole, camphor, imidazothiazole, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhydroacridine, dioxolane, dioxane, dithiolane, dithiane, dioxazine, dithiazine, 7-oxabicyclo[4.1.0]heptane.
Unless otherwise specified, all isomers are included in the present invention. For example, alkyl, alkenylene, alkynylene, alkoxy, and alkylene include straight-chain and branched-chain ones. Moreover, the isomers in the structure of a double bond, ring, fused ring (E, Z. cis, trans), the isomers generated by the presence of asymmetric carbon atom(s) etc. (R, S isomers, xcex1, xcex2 isomers, enantiomers, diastereomers) optically active isomers having optical rotation (D, L, d, 1 isomers), isomers separated by chromatography (more polar or less polar isomers), equilibrium compounds, compounds of arbitrary ratio of these compounds, racemic mixtures are included in the present invention.
[Salts]
Non-toxic salts of the compound (I) of the present invention include all pharmaceutically acceptable salts, for example, general salts, acid addition salts, hydrate salts.
The compounds of formula (I) and the present compounds of (1)xcx9c(47) may be converted into the corresponding salts. Non-toxic and water-soluble salts are preferred. Suitable salts, for example, include:
salts of alkali metals (e.g. potassium, sodium), salts of alkaline earth metals (e.g. calcium, magnesium), ammonium salts, salts of pharmaceutically acceptable organic amines (e.g. tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine, arginine, N-methyl-D-glucamine).
The compounds of the present invention of formula (I) and the present compound (1)-compound (47) may be converted into the corresponding acid addition salts. Non-toxic salts and water-soluble salts are preferred. Suitable salts, for example, include:
salts of inorganic acids e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate; salts of organic acids e.g. acetate, trifluoroacetate, lactate, tartarate, oxalate, fumarate, maleate, citrate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, toluenesulphonate, isethionate, glucuronate, gluconate.
The compounds of the present invention of formula (I), the present compound (1)-compound (47) and salts thereof may be converted into the corresponding hydrates by conventional means.
In the compound of the formula (I), a preferred combination of R2, R3, R4, R5, R6 and R7 is that:
[1] R2 is C1-8 alkyl substituted by one or more groups selected from C3-8 alkenyloxy and C3-8 alkynyloxy, R3, R4, R5 and R7 are hydrogen, and R6 is 1) hydrogen, 2) C1-8 alkyl, 3)C2-8 alkenyl, 4) xe2x80x94OR11, 5) xe2x80x94SR11, 6) xe2x80x94NR12R13, 7) Cyc1, 8) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, 9) C2-8 alkenyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, 10) C2-8 alkynyl, 11) C1-8 alkyl substituted by one or more groups selected from C3-8 alkenyloxy and C3-8 alkynyloxy; specially preferred R6 is 8) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, 9) C2-8 alkenyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1;
[2] R2 is 2-propynyl, R3, R4, R5 and R7 are hydrogen, and R6 is 1) hydrogen, 2) C1-8 alkyl, 3) C2-8 alkenyl, 4) xe2x80x94OR11, 5) xe2x80x94SR11, 6) xe2x80x94NR12R13, 7) Cyc1, 8) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, 9) C2-8 alkenyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1; specially preferred R6 is 8) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, 9) C2-8 alkenyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1;
[3] R6 is C2-8 alkynyl, R3, R4, R5 and R7 are hydrogen, and R2 is 1) hydrogen, 2) C1-8 alkyl, 3) C2-8 alkenyl, 4) xe2x80x94OR11, 5) xe2x80x94SR11, 6) xe2x80x94NR12R13, 7) Cyc1, 8) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, 9) C2-8 alkenyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1; specially preferred R2 is 2) C1-8 alkyl, 8) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, 9) C2-8 alkenyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1;
[4] R2 is C2-8 alkynyl, R3, R4, R5 and R7 are hydrogen, and R6 is C2-8 alkynyl;
[5] R2is C2 alkynyl (ethynyl), 1-propynyl, C4-8 alkynyl (butynyl, pentynyl, hexynyl, heptynyl, octynyl or isomeric groups thereof), R3, R4, R5 and R7are hydrogen, and R6 is 1) hydrogen, 2) C1-8 alkyl, 3) C2-8 alkenyl, 4) xe2x80x94OR11, 5) xe2x80x94SR11, 6) xe2x80x94NR12R13, 7) Cyc1, 8) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, 9) C2-8 alkenyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1; specially preferred R6 is 8) C1-8 alkyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14, guanidino and Cyc1, 9) C2-8 alkenyl substituted by one or more groups selected from xe2x80x94OR11, xe2x80x94SR11, xe2x80x94NR12R13, xe2x80x94COR14.
In the compound of formula (I), preferred are the compound of the formula (Ia) 
wherein G1 is methyl, halogen atoms, nitro, cyano or phenoxy, and the other symbols are as hereinbefore defined; or the compound of the formula (Ib): 
wherein G2 is methyl, halogen atoms, nitro or cyano, the other symbols are as hereinbefore defined.
Concretely, the compounds in the Table 1-Table 25, non-toxic salts thereof and the compounds described in Example are preferable. Besides, in the following table, EOM means ethoxymethyl, a mark xe2x80x9c*xe2x80x9d in the formula means an asymmetric carbon, and each of R, S and RS isomers is included.
[Process for the Preparation]
The compounds of the present invention of the formula (I), may be prepared by following methods or the methods described in the Examples.
[1] The compound in which R1 is xe2x80x94COOR10, that is the compound of the formula (I-1) 
wherein all the symbols are as hereinbefore defined; may be prepared by following methods (a)-(c).
(a) The compound in which xe2x80x94COOR10 of R1 is not xe2x80x94COOH, and all of R2, R3, R4, R5, R6, R7, R8 and R9 are not hydroxy, amino, or a group including xe2x80x94COOH, hydroxy or amino, that is the compound of the formula (I-1a): 
wherein R10-1a is C1-8 alkyl, C2-8 alkenyl, phenyl, C1-8 alkyl substituted by phenyl or C1-8 alkoxy, oxycarbonyl substituted by phenyl, benzyl or C1-8 alkyl, each of R2-1a, R3-1a, R4-1a, R5-1a, R6-1a, R7-1a, R8-1a and R9-1a is the a same meaning as R2, R3, R4, R5, R6, R7, R8 and R9, with the proviso that, all of R2-1a, R3-1a, R4-1a, R5-1a, R6-1a, R7-1a, R8-1a, R9-1a are not hydroxy, amino, or group including xe2x80x94COOH, hydroxy or amino, and the other symbols are as hereinbefore defined;
may be prepared by amidation of the compound of the formula (II): 
wherein all the symbols are as hereinbefore defined;
with the compound of the formula (III): 
wherein all the symbols are as hereinbefore defined.
The method of amidation of the compound of the formula (II) with the compound of the formula (III) is known. It includes the method
(1) via an acyl halide,
(2) via a mixed acid anhydride,
(3) using a condensing agent.
These methods are explained as follows.
(1) The method via an acyl halide, for example, may be carried out in an organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) or without a solvent, using an acyl halide (e.g. oxalyl chloride or thionyl chloride etc.) at xe2x88x9220xc2x0 C. to reflux temperature, and the obtained acyl halide derivative may be reacted with an amine in an organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) in the presence of a tertiary amine (e.g. pyridine, triethyl amine, dimethyl aniline or dimethylaminopyridine) at 0-40xc2x0 C.
(2) The method via a mixed acid anhydride may be carried out, for example, by reacting a carboxylic acid with an acyl halide (e.g. pivaloyl chloride, tosyl chloride or mesyl chloride) or an acid derivative (e.g. ethyl chloroformate or isobutyl chloroformate) in an organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) or without a solvent, in the presence of a tertiary amine (e.g. pyridine, triethylamine, dimethylaniline or dimethylaminopyridine) at 0-40xc2x0 C., and the obtained mixed acid anhydride derivative may be reacted with a corresponding amine in an organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) at 0-40xc2x0 C.
(3) The method using a condensing agent (e.g. 1,3-dicyclohexyl carbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propl]carbodiimide (EDC), 1,1xe2x80x2-carbonyldiimidazole (CDI) or 2-chloro-1-methylpyridinium iodide) maybe carried out, for example, by reacting a carboxylic acid with an amine in an organic solvent (e.g. chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran) or without a solvent, optionally in the presence of a tertiary amine (e.g. pyridine, triethylamine, dimethylaniline or dimethylaminopyridine) using a condensing agent, and optionally in the presence of 1-hydroxybenzotriazole (HOBt) at 0-40xc2x0 C.
The reaction described in (1), (2) and (3) may be carried out under an inert gas (e.g. argon, nitrogen) to avoid water in order to obtain a preferable result.
Besides, a different ester of the formula (I-1a) may be prepared by subjecting the compound of the formula (I-1aa) 
wherein all the symbols are as hereinbefore defined;
that was obtained by deprotection under alkaline conditions, deprotection under acidic conditions, hydrogenelysis, or deprotection of allyl ester from the compound of the formula (I-1a); to esterification reaction.
The esterification reaction is known, for example, it may be carried out in organic solvent (e.g. acetone, acetonitrile, DMF), in the presence of alkali carbonate (e.g. potassium carbonate, sodium carbonate, cesium carbonate), using a catalyst (e.g. sodium iodide) or without a catalyst, at 0-100xc2x0 C.
Further, the compound of the formula (I-1a) may be also prepared by reacting the compound of the formula (I-1a) in which R8-1a is hydrogen, that is the compound of the formula (I-1ab) 
wherein all the symbols are as hereinbefore defined;
with the compound of the formula (XIII)
Xxe2x80x94R8-1abxe2x80x83xe2x80x83(XIII)
wherein X is halogen atoms, R8-1ab is the same meaning as R8-1a, with the proviso that it is not represented hydrogen, and by reacting the compound of the formula (I-1a) in which R2-1a is hydrogen, that is the compound of the formula (I-1ac) 
wherein all the symbols are as hereinbefore defined;
with the compound of the formula (XIV)
Xxe2x80x94R2-1axe2x80x83xe2x80x83(XIV)
wherein all the symbols are as hereinbefore defined.
Furthermore, the compound of the formula (I-1a) maybe also prepared by reacting the compound of the formula (I-1ac) in which R8-1a is hydrogen, with the compound of the formula (XIV) and then the compound of the formula (XIII)
Xxe2x80x94R8-1abxe2x80x83xe2x80x83(XIII)
wherein all the symbols are as hereinbefore defined.
The reaction of the compound of the formula (I-1lab) and the compound of the formula (XIII), and the compound prepared by reacting the compound in which R8-1a is hydrogen in the compound of the formula (I-1ac) with the compound of the formula (XIV), and the compound of the formula (XIII), is known, for example, may be carried out in an organic solvent (e.g. THF), in the presence of a base (e.g. sodium hydroxide), at xe2x88x9220-50xc2x0 C.
The reaction of the compound of the formula (I-1ac) and the compound of the formula (XIV), for example, may be carried out in an organic solvent (e.g. THF, ethyleneglycol dimethyl ether), in the presence of a base (e.g. lithium bis (trimethylsilyl) amide, lithium diisopropylamide), adding an addition (e.g. 1,3-dimethyl-2-imidazolidinone, hexamethylphospholamide) or without an addition, at xe2x88x9278xc2x0 C.
(b) The compound in which xe2x80x94COOR10 of R1 is not xe2x80x94COOH, and at least one of R2, R3, R4, R5, R6, R7, R8 and R9 is hydroxy, amino, or a group including xe2x80x94COOH, hydroxy or amino, that is the compound of the formula (I-1b): 
wherein each of R2-1b, R3-1b, R4-1b, R5-1b, R6-1b, R7-1b, R8-1b, R9-1b is the a same meaning as R2, R3, R4, R5, R6, R7, R8, R9, with the proviso that, at least one of R2-1b, R3-1b, R4-1b, R5-1b, R6-1b, R7-1b, R8-1b, R9-1b is hydroxy, amino, or a group including xe2x80x94COOH, hydroxy or amino, and the other symbols are as hereinbefore defined;
may be prepared by deprotection under alkaline conditions, deprotection under acidic conditions, deprotection of a silyl group or hydrogenolysis of the compound having protected hydroxy or amino, or groups including protected xe2x80x94COOH, hydroxy or amino in the compound of the formula (I-1a), that is the compound of the formula (I-1a1): 
wherein each of R2-1a1, R3-1a1, R4-1a1, R5-1a1, R6-1a1, R7-1a1, R8-1a1, R9-1a1 is the a same meaning as R2, R3, R4, R5, R6, R7, R8, R9, with the proviso that, at least one of R2-1a1, R3-1a1, R4-1a1, R5-1a1, R6-1a1, R7-1a1, R8-1a1, R9-1a1 is protected hydroxy (e.g. protected by methoxymethyl, ethoxymethyl, methoxyethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl, benzyl), protected amino (e.g. protected by benzyloxycarboyl, t-butoxycarbonyl, trifluoroacetyl), or a group including protected xe2x80x94COOH (e.g. protected by methyl, ethyl, t-butyl and benzyl), protected hydroxy or protected amino, and the other symbols are as hereinbefore defined.
Deprotection under alkaline conditions is known, for example, it may be carried out in an organic solvent (e.g. methanol, tetrahydrofuran or dioxane), using an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide or lithium hydroxide), an alkaline earth metal hydroxide (e.g. barium hydroxide or calcium hydroxide) or a carbonate (e.g. sodium carbonate or potassium carbonate), an aqueous solution thereof or mixture thereof at 0-40xc2x0 C.
Deprotection under acidic conditions is known, for example, it may be carried out in an organic solvent (e.g. methylene chloride, chloroform, dioxane, ethyl acetate, anisole), using an organic acid (e.g. acetic acid, trifluoroacetic acid, methanesulfonic acid or trimethylsilyl iodide), or an inorganic acid (e.g. hydrochloric acid or sulfuric acid) or a mixture thereof (e.g. hydrogen bromide in acetic acid) at 0-100xc2x0 C.
Deprotection of a silyl group is known, for example, it may be carried out in a water miscible organic solvent (e.g. tetrahydrofuran or acetonitrile), using tetrabutylammonium fluoride at 0-40xc2x0 C.
Hydrogenolysis is known, for example, it may be carried out in a solvent [e.g. ether (such as tetrahydrofuran, dioxane, dimethoxyethane or diethyl ether), alcohol (such as methanol or ethanol), benzene (such as benzene or toluene), ketone (such as acetone or methyl ethyl ketone), nitrile (such as acetonitrile), amide (such as dimethylformamide), water, ethyl acetate, acetic acid or two more mixture thereof], in the presence of a catalyst (e.g. palladium on carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, nickel or Raney-nickel), optionally in the presence of an inorganic acid (e.g. hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid or tetrafluoroboric acid) or an organic acid (e.g. acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid or formic acid), at ordinary or elevated pressure of hydrogen gas or ammonium formate at 0-200xc2x0 C. It has no difficulty in using a salt of acid, when it is carried out using an acid.
(c) The compound in which xe2x80x94COOR10 of R1 is xe2x80x94COOH, that is the compound of the formula (I-1c): 
wherein all the symbols are the same meaning as hereinbefore defined;
may be prepared by deprotection under alkaline conditions, deprotection under acidic conditions, hydrogenolysis or deprotection of allyl ester of the above compounds of the formula (I-1a) and the formula (I-1b).
The reaction of deprotection under alkaline conditions, deprotection under acidic conditions and hydrogenolysis are known and they may be carried out by the same method as hereinbefore described.
The reaction of deprotection of allyl ester is known, for example, it may be carried out in an organic solvent [e.g. ether (such as THF, dioxane, dimethoxyethane or diethyl ether), alcohol (such as methanol or ethanol), benzene (such as benzene or toluene), ketone (such as acetone or methyl ethyl ketone), nitrile (such as acetonitrile), amide (such as DMF)], in the presence of a catalyst (e.g. palladium, such as tetrakis(triphenylphosphin)palladium(0)), in the presence of secondary amine (e.g. morphorine, piperadine) or/and trimethylsilyl halide, at 0-100xc2x0 C.
[2] In the compounds of the present invention of the formula (I), the compound in which R1 is xe2x80x94CONHOR10 or xe2x80x94CONHNHR10, that is the compound of the formula (I-2): 
wherein R2-1 is xe2x80x94CONHOR10 or xe2x80x94CONHNHR10, and the other symbols are as hereinbefore defined; may be prepared by following methods (a) and (b).
(a) The compound in which R1 is xe2x80x94CONHOR10 or xe2x80x94CONHNHR10, and all of R2, R3, R4, R5, R6, R7, R8 and R9 are not a group including xe2x80x94COOH, that is the compound of the formula (I-2a): 
wherein each of R2-2a, R3-2a, R4-2a, R5-2a, R6-2a, R7-2a, R8-2a, R9-2a is the a same meaning as R2, R3, R4, R5, R6, R7, R8, R9, with the proviso that, all of R2-2a, R3-2a, R4-2a, R5-2a, R6-2a, R7-2a, R8-2a, R9-2a are not a group including xe2x80x94COOH, and the other symbols are as hereinbefore defined;
may be prepared by amidation of the compound of the above formula (I-1) in which R1 is COOH, and all of R2, R3, R4, R5, R6, R7, R8, R9, are not a group including xe2x80x94COOH, that is the compound of the formula (I-1d): 
wherein all the symbols are as hereinbefore defined;
with the compound of the formula (IV):
H2Nxe2x80x94OR10xe2x80x83xe2x80x83(IV)
wherein R10 is as hereinbefore defined;
or the compound of the formula (V):
H2Nxe2x80x94NHR10xe2x80x83xe2x80x83(V)
wherein R10 is the same meaning as hereinbefore defined;
if necessary, continuously, by deprotection under alkaline conditions and/or deprotection under acidic conditions and/or hydrogenolysis.
This reaction of amidation, the reactions of deprotection under alkaline conditions, deprotection under acidic conditions and hydrogenolysis are known, and may be carried out by the same method as hereinbefore described.
(b) The compound in which R1 is xe2x80x94CONHOR10 or xe2x80x94CONHNHR10, and at least one of R2, R3, R4, R5, R6, R7, R8 and R9 is a group including xe2x80x94COOH, that is the compound of the formula (I-2b) 
wherein each of R2-2b, R3-2b, R4-2b, R5-2b, R6-2b, R7-2b, R8-2b, R9-2b is the a same meaning as R2, R3, R4, R5, R6, R7, R8, R9, with the proviso that, at least one of R2-2b, R3-2b, R4-2b, R5-2b, R6-2b, R7-2b, R8-2b, R9-2b is a group including xe2x80x94COOH, and the other symbols are as hereinbefore defined;
may be prepared by deprotection under alkaline conditions, deprotection under acidic conditions or hydrogenolysis of the compound of the above formula (I-2a) having a group including protected xe2x80x94COOH, that is the compound of the formula (I-2a1) 
wherein each of R2-2a1, R3-2a1, R4-2a1, R5-2a1, R6-2a1, R7-2a1, R8-2a1, R9-2a1 is the a same meaning as R2, R3, R4, R5, R6, R7, R8, R9, with the proviso that, at least one of R2-2a1, R3-2a1, R4-2a1, R5-2a1, R6-2a1, R7-2a1, R8-2a1, R9-2a1 is a group including protected xe2x80x94COOH (e.g. protected by methyl, ethyl, t-butyl and benzyl), and the other symbols are as hereinbefore defined.
The reactions of deprotection under alkaline conditions, deprotection under acidic conditions and hydrogenolysis are known, and may be carried out by the same method as hereinbefore described.
[3] In the compounds of the present invention of the formula (I), the compound in which R1 is xe2x80x94(CH2)nSR50, that is the compound of the formula (I-3) 
wherein R1-3 is xe2x80x94(CH2)nSR50, and the other symbols are as hereinbefore defined;
xe2x80x83may be prepared by following methods (a) and (b).
(a) The compound in which R1 is xe2x80x94(CH2)nSR50, and all of R2, R3, R4, R5, R6, R7, R8 and R9 are not hydroxy, amino, or a group including xe2x80x94COOH, hydroxy or amino, that is the compound of the formula (I-3a) 
wherein each of R2-3a, R3-3a, R4-3a, R5-3a, R6-3a, R7-3a, R8-3a, R9-3a is the a same meaning as R2, R3, R4, R5, R6, R7, R8, R9, with the proviso that, all of R2-3a, R3-3a, R4-3a, R5-3a, R6-3a, R7-3a, R8-3a, R9-3a are not hydroxy, amino, or a group including xe2x80x94COOH, hydroxy or amino, and the other symbols are as hereinbefore defined;
may be prepared by reaction of the compound of the formula (VI) 
wherein X is halogen atoms and the other symbols are as hereinbefore defined;
with the compound of the formula (VII)
R501SKxe2x80x83xe2x80x83(VII)
wherein R501 is C1-8 alkyl, xe2x80x94COR52, xe2x80x94SR531, in which R531 is C1-8 alkyl or phenyl.
The compound of the formula (I-3a) in which R50 is hydrogen or xe2x80x94SH may be prepared by a reaction of deprotection of the compound obtained by the above method.
The above method is known, for example, it may be carried out by refluxing in an organic solvent (e.g. acetone, tetrahydrofuran).
The continuous reaction, that is deprotection is known, for example, it may be carried out in an organic solvent (e.g. methanol, tetrahydrofuran or dioxane), using an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide or lithium hydroxide), an alkaline earth metal hydroxide (e.g. barium hydroxide or calcium hydroxide) or a carbonate (e.g. sodium carbonate or potassium carbonate), an aqueous solution thereof or mixture thereof at 0-40xc2x0 C.
(b) The compound in which R1 is xe2x80x94(CH2)nSR50, and at least one of R2, R3, R4, R5, R6, R7, R8 and R9 is a group including xe2x80x94COOH, hydroxy or a group including it, amino or a group including it, that is the compound of the formula (I-3b) 
wherein each of R2-3b, R3-3b, R4-3b, R5-3b, R6-3b, R7-3b, R8-3b, R9-3b is the a same meaning as R2, R3, R4, R5, R6, R7, R8, R9, with the proviso that, at least one of R2-3b, R3-3b, R4-3b, R5-3b, R6-3b, R7-3b, R8-3b, R9-3b is hydroxy, amino, or a group including xe2x80x94COOH, hydroxy or amino, and the other symbols are as hereinbefore defined;
may be prepared by deprotection under alkaline conditions, deprotection under acidic conditions or hydrogenolysis of the compound of the above formula (I-3a) having protected hydroxy, protected amino, or a group including protected xe2x80x94COOH, hydroxy or amino, that is the compound of the formula (I-3a1) 
wherein each of R2-3a1, R3-3a1, R4-3a1, R5-3a1, R6-3a1, R7-3a1, R8-3a1, R9-3a1 is the a same meaning as R2, R3, R4, R5, R6, R7, R8, R9, with the proviso that, at least one of R2-3a1, R3-3a1, R4-3a1, R5-3a1, R6-3a1, R7-3a1, R8-3a1, R9-3a1 is protected hydroxy (e.g. protected by methoxymethyl, ethyoxymethyl, methoxyethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl or benzyl), or protected amino (e.g. protected by benzyloxycarboyl, t-butoxycarbonyl, trifluoroacetyl), or a group including protected xe2x80x94COOH (e.g. protected by methyl, ethyl, t-butyl and benzyl), protected hydroxy or protected amino, and the other symbols are as hereinbefore defined.
The reactions of deprotection under alkaline conditions, deprotection under acidic conditions and hydrogenolysis are known, and may be carried out by the same method as hereinbefore described.
[4] In the compounds of the present invention of the formula (I) , the compound in which R1 is xe2x80x94Yxe2x80x94PO(OR51)2, that is the compound of the formula (I-4) 
wherein R1-4 is xe2x80x94Yxe2x80x94PO(OR51)2, and the other symbols are as hereinbefore defined;
xe2x80x83may be prepared by following methods (a)-(d).
(a) The compound in which R1 is xe2x80x94Y1xe2x80x94PO(OR51)2, in which Y1 is xe2x80x94Oxe2x80x94 and the other symbols are as hereinbefore defined; and all of R2, R3, R4, R5, R6, R7, R8 and R9 are not hydroxy, amino, or a group including xe2x80x94COOH, hydroxy or amino, that is the compound of the formula (I-4a) 
wherein each of R2-4a, R3-4a, R4-4a, R5-4a, R6-4a, R7-4a, R8-4a, R9-4a is the a same meaning as R2, R3, R4, R5, R6, R7, R8, R9, with the proviso that, all of R2-4a, R3-4a, R4-4a, R5-4a, R6-4a, R7-4a, R8-4a, R9-4a are not hydroxy, amino, or a group including xe2x80x94COOH, hydroxy or amino, and the other symbols are as hereinbefore defined;
may be prepared by reaction of the compound of the formula (VIII) 
wherein all the symbols are as hereinbefore defined;
with the compound of the formula (IX) 
wherein R511 is C1-8 alkyl, phenyl or a known protecting group of phosphoric acid and the other symbols are as hereinbefore defined;
when using the compound of the formula (IX) in which R511 is protected phosphoric acid, continuously, by deprotection.
The above reaction is known, for example, it may be carried out in an organic solvent (e.g. pyridine) at 0-40xc2x0 C.
The reaction of deprotection of phosphoric acid is known, for example, it may be carried out in an organic solvent (e.g. pyridine), using zinc acetate at 0-40xc2x0 C.
(b) The compound in which R1 is xe2x80x94Y1xe2x80x94PO(OR51)2, and at least one of R2, R3, R4, R5, R6, R7, R8 and R9 is hydroxy, amino, or a group including xe2x80x94COOH, hydroxy or amino, that is the compound of the formula (I-4b) 
wherein each of R2-4b, R3-4b, R4-4b, R5-4b, R6-4b, R7-4b, R8-4b, R9-4b is the a same meaning as R2, R3, R4, R5, R6, R7, R8, R9, with the proviso that, at least one of R2-4b, R3-4b, R4-4b, R5-4b, R6-4b, R7-4b, R8-4b, R9-4b is hydroxy, amino, or a group including xe2x80x94COOH, hydroxy or amino, and the other symbols are as hereinbefore defined;
may be prepared by deprotection under alkaline conditions, deprotection under acidic conditions or hydrogenolysis of the compound of the above formula (I-4a) having a group including protected hydroxy, protected amino, or a group including protected xe2x80x94COOH, protected hydroxy or protected amino, that is the compound of the formula (I-4a1) 
wherein each of R2-4a1, R3-4a1, R4-4a1, R5-4a1, R6-4a1, R7-4a1, R8-4a1, R9-4a1 is the a same meaning as R2, R3, R4, R5, R6, R7, R8, R9, with the proviso that, at least one of R2-4a1, R3-4a1, R4-4a1, R5-4a1, R6-4a1, R7-4a1, R8-4a1, R9-4a1 is protected hydroxy (e.g. protected by methoxymethyl, ethoxymethyl, methoxyethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl, benzyl), protected amino (e.g. protected by benzyloxycarboyl, t-butoxycarbonyl, trifluoroacetyl), or a group including protected xe2x80x94COOH (e.g. protected by methyl, ethyl, t-butyl and benzyl), protected hydroxy or protected amino, and the other symbols are as hereinbefore defined.
The reactions of deprotection under alkaline conditions, deprotection under acidic conditions and hydrogenolysis are known, and may be carried out by the same method as hereinbefore described.
(c) The compound in which R1 is xe2x80x94Y2xe2x80x94PO(OR51)2, in which Y2 is a single bond or xe2x80x94CH2xe2x80x94 and the other symbols are as hereinbefore defined; and all of R2, R3, R4, R5, R6, R7, R8 and R9 are not hydroxy, amino, or a group including xe2x80x94COOH, hydroxy or amino, that is the compound of the formula (I-4c) 
wherein each of R2-4c, R3-4c, R4-4c, R5-4c, R6-4c, R7-4c, R8-4c, R9-4c is the a same meaning as R2, R3, R4, R5, R6, R7, R8, R9, with the proviso that, all of R2-4c, R3-4c, R4-4c, R5-4c, R6-4c, R7-4c, R8-4c, R9-4c are not hydroxy, amino or a group including xe2x80x94COOH, hydroxy or amino, and the other symbols are as hereinbefore defined;
may be prepared by reaction of the compound of the formula (X): 
wherein all the symbols are as hereinbefore defined;
with the compound of the formula (XI)
(R511O)3Pxe2x80x83xe2x80x83(XI)
or the compound of the formula (XII)
(R511O)2POKxe2x80x83xe2x80x83(XII)
wherein all the symbols are as hereinbefore defined;
when using the compound of the formula (XI) or the compound of the formula (XII) in which R511 is protected phosphoric acid, continuously, by deprotection.
The above reaction is known, for example, it maybe carried out in an organic solvent (e.g. tetrahydrofuran, dimethylformamide) at 0-120xc2x0 C.
The reaction of deprotection of phosphoric acid is known, and it may be carried out by the same method as hereinbefore described.
(d) The compound in which R1 is xe2x80x94Y2xe2x80x94PO(OR51)2, and at least one of R2, R3, R4, R5, R6, R7, R8 and R9 is hydroxy, amino, or a group including xe2x80x94COOH, hydroxy or amino, that is the compound of the formula (I-4d) 
wherein each of R2-4d, R3-4d, R4-4d, R5-4d, R6-4d, R7-4d, R8-4d, R9-4d is the a same meaning as R2, R3, R4, R5, R6, R7, R8, R9, with the proviso that, at least one of R2-4d, R3-4d, R4-4d, R5-4d, R6-4d, R7-4d, R8-4d, R9-4d is hydroxy, amino, or a group including xe2x80x94COOH, hydroxy or amino, it, and the other symbols are as hereinbefore defined; may be prepared by deprotection under alkaline conditions, deprotection under acidic conditions or hydrogenolysis of the compound of the above formula (I-4c) having protected a group including protected hydroxy, protected amino or a group including protected xe2x80x94COOH, hydroxy or amino, that is the compound of the formula (I-4c1) 
wherein each of R2-4c1, R3-4c1, R4-4c1, R5-4c1, R6-4c1, R7-4c1, R8-4c1, R9-4c1 is the a same meaning as R2, R3, R4, R5, R6, R7, R8, R9, with the proviso that, at least one of R2-4c1, R3-4c1, R4-4c1, R5-4c1, R6-4c1, R7-4c1, R8-4c1, R9-4c1 is protected hydroxy, protected amino or a group including protected xe2x80x94COOH (e.g. protected by methyl, ethyl, t-butyl and benzyl), protected hydroxy or protected amino and the other symbols are as hereinbefore defined.
The reactions of deprotection under alkaline conditions, deprotection under acidic conditions and hydrogenolysis are known, and may be carried out by the same method as hereinbefore described.
The reactions of deprotection in the present invention are a common reactions of deprotection as will be apparent to those skilled in the art, for example, deprotection under alkaline conditions, deprotection under acidic conditions or hydrogenolysis. The desired compound of the present invention may be easily prepared using these protecting groups.
As will be apparent to those skilled in the art, methyl, ethyl, t-butyl or benzyl may be used protecting groups for carboxyl, but other groups, which may be removed easily and selectively, are also preferred. For example, the groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, N.Y., 1991, may be used.
Methoxymethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl or benzyl may be used protecting groups for hydroxy, but other groups, which may be removed easily and selectively, are also preferred. For example, the groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, N.Y., 1991, may be used.
Benzyloxycarbonyl, t-butoxycarbonyl or trifluoroacetyl may be used as protecting groups for amino, but other groups which may be removed easily and selectively are also preferred. For example, the groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, N.Y., 1991, may be used.
The compounds of the formulae (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) , (XI), (XII), (XIII) and (XIV) are known per se or may be prepared by known methods.
In each reaction in the present specification, products may be purified by conventional techniques. For example, purification may be carried out by distillation at atmospheric or reduced pressure, by high performance liquid chromatography, by thin layer chromatography or by column chromatography using silica gel or magnesium silicate, by washing or by recrystallization. Purification may be carried out after each reaction, or after a series of reactions.
[Pharmacological Activities]
The potency of inhibitory activity against each matrix metalloproteinases of the compound of the formula (I) was confirmed as below.
(1) Inhibitory Activity Against Gelatinase A
Method
The progelatinase A (5 xcexcl; in assay buffer (40 xcexcl)) was purified from human normal skin dermal fibroblasts (HNDF). It was activated by adding thereto 10 mM of p-aminophenylmercuric acetate (APMA) (5 xcexcl) and preincubating for 1 hour at 37xc2x0 C.
A mixture of the synthetic substrate (MOCAc-Pro-Leu-Gly-A2pr(Dnp)-Ala-Arg-NH2) (130 xcexcl; a final concentration 13.5 xcexcM) and a solution (20 xcexcl) with or without various concentrations of the test compound was preincubated for 5 minutes at 37xc2x0 C.
The solution of activated gelatinase A (50 xcexcl/well) was mixed with the mixture and the mixture was incubated for 15 minutes at 37xc2x0 C. The enzyme reaction was started. The enzyme activity was represented by increasing value of fluorescent intensity [Ex=325 nm (Ex)/393 nm (Em)] per 1 minute. Inhibitory activity was represented by inhibitory percentage (%) per enzyme activity without the test compound.
The result was showed in Table 26.
(2) Inhibitory Activity Against Collagenase
Method
The procollagenase (5 xcexcl; in assay buffer (105 xcexcl)) was purified from human normal skin dermal fibroblasts (HNDF). It was activated by adding thereto 1 mg/ml Trypsin (45 xcexcl) and preincubating for 1 minute at 37xc2x0 C. Trypsin was inactivated by addition of 5 mg/ml soybean trypsin inhibitor (SBTI; 50 xcexcl).
A mixture of the synthetic substrate (Ac-Pro-Leu-Gly-[2-mercapto-4-methyl-pentanoyl]-Leu-Gly-OEt) (105 xcexcl; a final concentration 1.33 mM) and a solution (20 xcexcl) with or without various concentrations of the test compound was preincubated for 5 minutes at 26xc2x0 C.
The solution of activated enzyme (75 xcexcl /tube, 50 xcexcl) was mixed with the mixture and the mixture was incubated for 10 minutes at 26xc2x0 C.
Absorption at 324 nm was measured 40 points in the course of 10 minutes. Vmax value was determined as measured value in 30 points therein.
The result was showed in Table 27.
(3) Inhibitory Activity Against Stromelysin
Method
The mixture of human stromelysin (Yagai; 9 volume) and 10 mM p-aminophenylmercury acetate (1 volume) was activated for 20 hours at 37xc2x0 C. A solution of the test compound in dimethylsulfoxide (10 xcexcl) and 0.5 mM solution (10 xcexcl) of 10 mM solution of the synthetic substrate NFF-3 (Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(DNP)-NH2., Nva: norvaline, Peptide Laboratory) in dimethylsulfoxide diluted by water were added to assay buffer (50 mM tris-HCl, 10 mM CaCl2, 0.05% Brij35, 0.02% NaN3 (pH7.5)) (150 xcexcl). Furthermore, assay buffer (30 xcexcl) was added to the mixture. The mixture was incubated for 10 minutes at 37xc2x0 C. The reaction was started by addition of a solution of the above activated stromelysin solution (50 xcexcl). The enzyme activity was represented by increasing value of fluorescent intensity [Ex=325 nm (Ex)/393 nm (Em)] per 1 minute. Inhibitory activity was represented by inhibitory percentage (%) per enzyme activity without the test compound.
The result was showed in Table 28.
[Toxicity]
The toxicity of the compounds of the present invention is very low and therefore, the compounds may be considered safe for pharmaceutical use.
[Application for Pharmaceuticals]
Inhibition of matrix metalloproteinase, for example, gelatinase, stromelysin or collagenase, is useful for prevention and/or treatment of diseases, for example, rheumatoid diseases, arthrosteitis, osteoarthritis, unusual bone resorption, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, cornea ulcer, metastasis, invasion or growth of tumor cells, autoimmune disease (Crohn""s disease, Sjogren""s syndrome), disease caused by vascular emigration or infiltration of leukocytes, arterialization, multiple sclerosis, aorta aneurysm, endometriosis, restenosis after PTCA, unstable angina, acute myocardial infarction, transient ischemic attack in animals including human beings, especially human beings.
For the purpose above described, the compounds of formulae (I) of the present invention and non-toxic salts, acid addition salts or hydrates may be normally by administered systemically or locally usually by oral or parenteral administration.
The doses to be administered are determined depending upon, for example, age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment. In the human adult, the doses per person are generally from 1 mg to 1000 mg, by oral administration, up to several times per day, and from 0.1 mg to 100 mg, by parenteral administration (preferably intravenous administration), up to several times per day, or continuous administration from 1 to 24 hours per day from vein.
As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
The compounds of the present invention may be administered in the form of, for example, solid forms for oral administration, liquid forms for oral administration, injections, liniments or suppositories for parenteral administration.
Solid forms for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules. Capsules include hard capsules and soft capsules.
In such solid forms, one or more of the active compound(s) maybe admixed with vehicles (such as lactose, mannitol, glucose, microcrystalline cellulose, starch), binders (such as hydroxypropyl cellulose, polyvinylpyrrolidone or magnesium metasilicate aluminate), disintegrants (such as cellulose calcium glycolate), lubricants (such as magnesium stearate), stabilizing agents, and solution adjuvants (such as glutamic acid or aspartic acid) and prepared according to methods well known in normal pharmaceutical practice. The solid forms may, if desired, be coated with coating agents (such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
Liquid forms for oral administration include pharmaceutically acceptable solutions, suspensions and emulsions, syrups and elixirs. In such forms, one or more of the active compound(s) may be dissolved, suspended or emulized into diluent(s) commonly used in the art (such as purified water, ethanol or a mixture thereof). Besides such liquid forms may also comprise some additives, such as wetting agents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, aroma, preservative or buffering agent.
Injections for parenteral administration include sterile aqueous, suspensions, emulsions and solid forms which are dissolved or suspended into solvent(s) for injection immediately before use. In injections, one or more of the active compound(s) may be dissolved, suspended or emulized into solvent(s). The solvents may include distilled water for injection, physiological salt solution, vegetable oil, propylene glycol, polyethylene glycol, alcohol, e.g. ethanol, or a mixture thereof.
Injections may comprise some additives, such as stabilizing agents, solution adjuvants (such as glutamic acid, aspartic acid or POLYSORBATE80 (registered trade mark)), suspending agents, emulsifying agents, soothing agent, buffering agents, preservative. They may be sterilized at a final step, or may be prepared and compensated according to sterile methods. They may also be manufactured in the form of sterile solid forms which may be dissolved in sterile water or some other sterile diluent(s) for injection immediately before use.
Other forms for parenteral administration include liquids for external use, ointments and endermic liniments, inhalations, sprays, suppositories and pessaries for vaginal administration which comprise one or more of the active compound(s) and may be prepared by methods known per se. Sprays may comprise additional substances other than diluents, such as stabilizing agents (such as sodium sulfate), isotonic buffers (such as sodium chloride, sodium citrate or citric acid). For preparation of such sprays, for example, the method described in the U.S. Pat. No. 2,868,691 or U.S. Pat. No. 3,095,355 may be used.